Treatment options for recurrent prostate cancer Jennifer L. Young MD The Urology Group Prostate Cancer Support Group January 13, 2014 Reston Hospital

S THE UROLOGY GROUP

Treatment options for recurrent prostate cancer S  Background S  Radiation S  Hormone treatment S  Chemotherapy S  New agents

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Treatment options for recurrent prostate cancer

S  Background S  Radiation S  Hormone treatment S  Chemotherapy S  New agents

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Background

S  Prostate cancer is the most commonly diagnosed solid organ

cancer in the United States S  240,000 in 2012

S  Prostate cancer is the second leading cause of cancer deaths

among American men S  28,000 in 2012

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Yesterday and today 1975

2007

S  94 new cases per 100,000 men

S  116 cases per 100,000 men

S  31 deaths per 100,000 men

S  24 deaths per 100,000 men

S  1986 FDA approves PSA

S  90% of cancers diagnosed at

S  Increase in diagnosis

early stage

S  1992: peaked at 237 cases per

100,000 men

www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/prostate

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PSA came into use 1980s – increased incidence of prostate cancer

www.cancer.gov/researchandfunding/ snapshots/prostate

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Treatment localized cancer 1975 S  Surgery S  Open prostatectomy S  Radiation S  External beams

2007 S  Surgery S  Nerve-sparing prostatectomy S  Laparoscopic and robotic

prostatectomy

S  Radiation S  External beams S  Seeds (brachytherapy) S  Active surveillance for early, low

grade cancer

www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/prostate

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Hormone therapy 1975 S  Removal of the testicles

2007 S 

S 

S  Estrogen S  Diethylstilbestrol (DES) S  Cardiovascular side

1985: Gonadotropin-releasing hormone agonists

S 

1997: Anti-androgens S 

effects S 

bicalutamide (Casodex), flutamide (Eulexin), nilutamide (Nilandron)

2008: Gonadotropin-releasing hormone agonists S 

S 

leuprolide (Lupron), goserelin (Zoladex), triptorelin (Trelstar), histrelin (Vantas)

degarelix (Firmagon)

Ketoconazole (Nizoral)

www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/prostate

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Chemotherapy 1975 S  none

2007 S  2004: docetaxel

(Taxotere) S  2010: cabazitaxel

(Jevtana) S  Men who no longer respond to docetaxel

www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/prostate

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Immunotherapy 1975 S  none

2007 S  2010: sipuleucel T

(Provenge) vaccine

www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/prostate

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Bone agents 1975 S  none

2007 S  Bisphosphonates S  zolendronic acid (Reclast, Zometa), alendronate

(Fosamax), ibandronate (Boniva) risedronate (Actonel) S  Selective estrogen receptor modulators S  raloxifene (Evist) and toremifene (Fareston) S  Teriparatide (Forteo) S  RANK ligand inhibitor S  denosumab (Xgeva, Prolia) S  Calcitonin American Urological Association 2013 San Diego, CA Annual Meeting Highlights. P 7-9

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Radiation to bone 1975 S  none

2013 S  Injectable radiation S  Radium-223

dichloride (Xofigo)

American Urological Association 2013 San Diego, CA Annual Meeting Highlights. P 7-9

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Prevention 1975 S  none

2007 S  2003: finasteride

(Proscar) decreases risk of prostate cancer 25% S  2010: dutasteride

(Avodart) decreases risk of prostate cancer in high risk men www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/prostate

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Background

S  The most common treatment for prostate cancer is surgery S  Radical prostatectomy

S  In 2/3 of men, prostatectomy cures prostate cancer S  In 1/3 of men, prostate cancer will come back within 10

years

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Why does it come back?

S  A microscopic amount of cancer cells left behind at surgery S  Spread of cancer outside the pelvis (low belly)

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Risks for recurrent cancer

S  Worrisome pathology after surgery S  Positive margins – cancer seen at edge of removed prostate S  Cancer in the glands behind the prostate (seminal vesicles) S  Cancer bulging outside the capsule of the prostate S  Higher Gleason score

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Treatment options for recurrent prostate cancer S  Background S  Radiation S  Hormone treatment S  Chemotherapy S  New agents

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New guidelines for radiation after surgery S  Radiation after Prostatectomy Panel S  American Urological Association Education and Research,

Inc. (AUA) S  American Society for Radiation Oncology (ASTRO) S  Panel created in 2011 S  Guidelines approved in 2013

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How can you tell when cancer has come back? S  Check PSA blood test regularly after surgery S  Rising PSA after surgery means a higher risk of: S  Spread of prostate cancer throughout the body (metastasis) S  Death from prostate cancer

S  Clinical Principle Guideline Statement 4. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

What PSA level indicates cancer has come back? S  Detectable or rising PSA value after surgery ≥ 0.2 ng/ml S  Second test that confirms PSA ≥ 0.2 ng/ml

S  Recommendation; Evidence Strength: Grade C Guideline Statement 5. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

Do I need any more tests?

S  Restaging evaluation may be considered S  Bone scan S  CT scan of the pelvis (low belly)

S  Option; Evidence Strength: Grade C Guideline Statement 6. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

Should I get radiation?

S  Radiation should be offered to men with PSA recurrence

after surgery if there is no evidence of distant spread of cancer (scans show prostate cancer, bone pain)

S  Recommendation; Evidence Strength: Grade C Guideline Statement 7. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

When should I get radiation?

S  Radiation for PSA recurrence is most effective when given

at lower levels of PSA

S  Clinical Principle Guideline Statement 8. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

What are the benefits of radiation? S  Potential benefits of controlling recurrent prostate cancer

Guideline Statement 9. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

What are the risks of radiation?

S  Short-term and long-term side effects S  Urinary: urinary frequency and urgency, blood in the urine,

scar tissue in the bladder tube S  Bowel: bowel frequency and urgency, diarrhea, blood in the stool S  Sexual: erectile dysfunction S  Clinical Principle Guideline Statement 9. Radiation after Prostatectomy: ASTRO/AUA Guideline THE UROLOGY GROUP

Treatment options for recurrent prostate cancer S  Background S  Radiation S  Hormone treatment S  Chemotherapy S  New agents

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Wilson SS and Glode LM. Appropriate use of androgen deprivation for the management of prostate cancer. AUA Update Series, Volume 30, Lesson 11. American Urological Association Education and Research, Inc, 2011.

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Hormone (androgen deprivation) therapy S  Hormone therapy is also called androgen deprivation therapy

(ADT) or androgen suppression therapy S  The goal is to reduce levels of male hormones, called

androgens, in the body, or to prevent them from reaching prostate cancer cells

www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treatinghormone-therapy

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S  The main androgens in men’s blood is testosterone and

dihydrotestosterone (DHT) S  85-90% is made in the testicles. 10-15% is made by the adrenal glands

and other parts of the body www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page2

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Hormone (androgen deprivation) therapy S  Androgens stimulate prostate cancer cells to grow S  Lowering androgen levels or stopping them from getting

into prostate cancer cells makes prostate cancers shrink or grow more slowly S  Hormone therapy alone does not cure prostate cancer S  Eventually hormone therapy stops working

www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treatinghormone-therapy

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Treatments to lower androgen levels S  Orchiectomy (surgical castration) S  Luteinizing hormone-releasing hormone (LHRH) analogs S  Similar to LHRH

S  Luteinizing hormone-releasing hormone (LHRH)

antagonists S  Block LHRH

www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormonetherapy

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Orchiectomy (surgical castration) S  Surgical removal of the testicles S  Outpatient surgery S  Simple, least expensive S  Permanent S  Testicle prostheses available

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S 

The brain sends chemical signals (LHRH/GnRH) to the pituitary gland

S 

The pituitary gland sends chemical signals (LH) to the testicles to make testosterone

S 

When testosterone is detected, these signals shut off

www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page2

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S  leuprolide (Lupron,

Viadur, Eligard) S  histrelin (Vantas) S  goserelin (Zoladex) S  triptorelin (Trelstar)

S 

LHRH agonists suppress the pituitary gland’s call for testosterone

S 

Injection in the muscle every 3 to 6 months

S 

Testosterone flare - bone pain, block ureter, spinal cord compression

www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page2

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S  degarelix (Firmagon) S  abarelix (Plenaxis) S  Withdrawn from US

2005, used in Germany

S  LHRH antagonists stop the production of testosterone in the testes and adrenal glands S  Injection into skin (belly) every 28 days S  No testosterone flare www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page2

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Drugs that stop androgens from working S  Anti-androgens S  casodex (bicalutamide), nilandron (nilutamide), eulexin

(flutamide) S  Androgen synthesis inhibitors (“super-antiandrogens”) S  Abiraterone (Zytiga)

S  Next generation androgen receptor blockers S  Enzalutamide (Xtandi)

www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormone-therapy

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S  casodex

(bicalutamide) S  nilandron (nilutamide) S  eulexin (flutamide)

S  Blocks androgens from androgen receptor S  Oral pills taken daily S  Usually given before treatment with, or in combination with, an LHRH agonist www.medscape.org/viewarticle/416543_6

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Other androgen-suppressing drugs S  estrogens (female hormones) S  Diethylstilbestrol (DES): cardiovascular side effects

S  ketoconazole (Nizoral) S  Dramatically decreases testosterone level in 4 hours

S  aminoglutethimide (Cytadren) S  Blocks steroid synthesis, including testosterone

www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormone-therapy http://www.healthline.com/health/prostate-cancer-drugs?toptoctest=expand

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Side effects of blocking testosterone S  Osteoporosis (bone thinning), broken

bones S  Reduced or absent libido (sexual desire) S  Impotence (erectile dysfunction) S  Shrinking of testicles and penis S  Hot flashes, may get better or even go

away with time

S  Decreased mental sharpness S  Loss of muscle mass S  Weight gain S  Fatigue S  Increased cholesterol, possible

cardiovascular problems (heart attack, death)

S  Breast tenderness, growth of breast tissue S  Depression S  Anemia (low red blood cell counts) www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormone-therapy

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Prevention

S  Calcium and vitamin D S  Regular, weight-bearing exercise S  Bone density scans

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When cancer no longer responds to hormone therapy S  Prostate cancer spreads throughout the body S  Historically, average survival was less than 2 years S  New treatments, longer survival S  Remains an incurable disease

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Treatment options for recurrent prostate cancer S  Background S  Radiation S  Hormone treatment S  Chemotherapy S  New agents

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Chemotherapy for prostate cancer S  For metastatic cancer (spread beyond the prostate), no

longer responsive to hormone therapy S  Kill cancer cells or prevent them from multiplying S  Given through the vein (intravenous) or by mouth

www.prostate.net/prostate-cancer/chemotherapy-for-prostate-cancer/

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Chemotherapy S  doxetaxel (Taxotere): intravenous, S  paclitaxel (Taxol): intravenous

with other drugs

S  cabazitaxel (Jevtana): injectable,

with prednisone, if no response to docetaxel. Approved 2010

S  mitoxantrone (Novantrone): with

steroids, treats pain in advanced cancer

S  estramustine (Emcyt): orally,

sometimes with other drugs

www.prostate.net/prostate-cancer/chemotherapy-for-prostate-cancer/

S  etoposide (Vepsid, V-16):

intravenous and by mouth, combined with other drugs

S  doxorubicin (Adriamycin):

intravenous, an antibiotic. Risk of heart damage.

S  vinblastine (Velban): intravenous,

often with other drugs

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docetaxel (Taxotere)

S  One of the main types of chemotherapy to treat hormone-

refractory prostate cancer S  Prevents cell growth S  Inhibits microtubule assembly and disassembly

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Cancer.gov

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docetaxel (Taxotere)

S  Effectiveness: S  17.5 month survival compared to 15.6 months with

mitoxantrone chemotherapy S  18.9 month survival compared to 16.5 month survival with

mitoxantrone

S  Side effects: 26% had serious side effects S  11% stopped treatment

SWOG 9916; TAX-327

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THE UROLOGY GROUP

Treatment options for recurrent prostate cancer S  Background S  Radiation S  Hormone treatment S  Chemotherapy S  New agents

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New agents

S  Immunotherapy S  Sipuleucel-T (Provenge)

S  Androgen blockers S  abiaterone (Zytiga) S  enzalutamide (Xtandi)

S  Injectable radiation S  Radium-223 dichloride (Xofigo)

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sipuleucel-T (Provenge)

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sipuleucel-T (Provenge)

S  Immunotherapy S  Approved by FDA 2010 S  First and only cancer vaccine ever approved by the FDA

IMPACT trial 2008

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sipuleucel-T (Provenge)

S  Autologous cellular immunotherapy, S  Uses a man’s own immune cells (autologous) to battle prostate

cancer S  Series of carefully orchestrated steps to make a drug that is

personalized for each patient

www.prostate.net/2012/prostate-cancer/provenge/

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sipuleucel-T (Provenge)

S  Other therapies work against the body S  Hormone therapy stops production of hormones S  Chemotherapy therapy are toxic and focus on killing cancer

cells S  Provenge is an approach that makes use of the body’s own

immune cells (dendritic or T cells) which have been activated in a lab so they can recognize and battle prostate cancer cells www.prostate.net/2012/prostate-cancer/provenge/

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sipuleucel-T (Provenge)

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Who can take sipuleucel-T (Provenge)? S  No or few symptoms: no cancer pain or, pain does not

require narcotic pain medicine S  Cancer has spread to other areas in the body, such as bone

(metastatic) S  Cancer has worsened despite hormone treatment (androgen

resistant) S  Lower amount of cancer, healthy immune system www.prostate.net/2012/prostate-cancer/provenge/ The National Comprehensive Care Network

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How sipuleucel-T (Provenge) is prepared S  Leukopharesis: blood drawn through a large vein, goes into a

machine where immune cells (dendritic or T cells), clotting proteins (platelets) and red blood cells are extracted. 3-4 hours

S  Cells sent to a lab where the are activated to prompt the immune

cells to look for and attack prostate cancer cells. 2- 3 days

S  Activated immune cells (personalized drug) is infused 3 days later.

2 hours

S  3 doses total. Treatment period: 5 weeks www.prostate.net/2012/prostate-cancer/provenge/

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sipuleucel-T (Provenge)

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S  The blood of the cancer patient is collected and enriched to

increase the population of immune cells (dendritic or T cells) www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page3

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S  These cells are then grown in the laboratory in the presence of a

protein or part of a protein that is present in or on the patient's tumor cells www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page3

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S  When the dendritic cells are put back into the patient, they signal the

body’s own immune system to destroy all cells with the telltale protein, including cancer cells www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/prostatecancer_htmlcourse/page3

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sipuleucel-T (Provenge)

S